(S)-4-halo-3-hydroxybutyric acid esters are compounds used as intermediates in synthesizing HMG-CoA reductase inhibitors, D-carnitine, etc. These compounds are useful for syntheses of medicines and pesticides. Especially, how to get (to synthesize or separate) optically pure enantiomers of (S)-4-halo-3-hydroxybutyric acid esters is industrially important problem. So far, asymmetric synthesis, crystallization, and asymmetric reduction method using microorganisms such as baker's yeast (Unexamined Published Japanese Patent Application (JP-A) Sho 61-146191, JP-A Hei 6-209782, and such) are known as methods for producing (S)-4-halo-3-hydroxybutyric acid esters. However, these known methods are inappropriate for industrial use because of the problems such as low optical purities of products, low yield, etc.
In addition, enzymes that reduce 4-haloacetoacetic acid esters to (S)-4-halo-3-hydroxybutyric acid esters are also being searched. For example, enzymes indicated below are known. The methods for synthesizing (S)-4-halo-3-hydroxybutyric acid esters using these enzymes are reported. These enzymes are, however, reductases that use reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) as a coenzyme. Therefore, synthesizing (S)-4-halo-3-hydroxybutyric acid esters using these enzymes requires addition and regeneration of NADPH, which is expensive and chemically unstable, and is industrially disadvantageous.                Some reductases derived from baker's yeast (D-enzyme-1, D-enzyme-2, J. Am. Chem. Soc., 107:2993–2994, 1985)        Aldehyde reductase 2 derived from Sporobolomyces salmonicolor (Appl. Environ. Microbiol., 65:5207–5211, 1999)        Keto pantothenic acid ester reductase derived from Candida macedoniensis (Arch. Biochem. Biophys., 294:469–474, 1992)        4-Chloroacetoacetic acid ethyl ester reductase derived from Geotrichum candidum (Enzyme Microb. Technol. 14, 731–738, 1992)        Carbonyl reductase derived from Candida magnoliae (WO 98/35025)        Carbonyl reductase derived from Kluyveromyces lactis (JP-A Hei 11-187869)        β-Ketoacyl-acyl carrier protein reductase as one of fatty acid synthases type II (JP-A 2000-189170)        
Although 3α-hydroxysteroid dehydrogenase (JP-A Hei 1-277494), glycerol dehydrogenase (Tetrahedron Lett. 29, 2453–2454, 1988), and alcohol dehydrogenase derived from Pseudomonas sp. PED (J. Org. Chem., 57:1526–1532, 1992) are known as reductases using reduced form of nicotinamide adenine dinucleotide (NADH) as a electron donor, these enzymes are industrially disadvantageous because the activity of reaction for synthesizing (S)-4-halo-3-hydroxybutyric acid esters is low.
As indicated above, known methods for producing (S)-4-halo-3-hydroxybutyric acid esters using microorganisms and enzymes were not satisfactory in some respects such as optical purities, yields, activities, etc. These problems have made known methods difficult for industrial use.
On the other hand, (R)-propoxybenzene derivatives (JP-A Hei 02-732) are useful compounds as intermediates in synthesizing medicines, especially, optically active substances of ofloxacin ((S)-(−)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzooxazine-6-carboxylic acid, JP-A Sho 62-252790), which is synthetic antibacterial drugs. How to get (to synthesize or separate) optically pure enantiomers of these compounds is industrially important problem.
Asymmetric acylation of racemates of propoxybenzene derivatives using lipase and esterase (JP-A Hei 03-183489) is known as a method for producing (R)-propoxybenzene derivatives. In this method, a process to separate remaining raw materials and acylated products after acylation of (R) form and a process to deacylate the acylated products are required. Therefore, this known method is inappropriate for industrial use because these processes are complicated.
The method for asymmetric reduction of acetonyloxybenzene derivatives using microorganisms has been also reported. However, this known method is inappropriate for industrial use because optical purities of (R)-propoxybenzene derivatives produced is as low as 84 to 98% (JP-A Hei 03-183489) or 8.8 to 88.4% (JP-A Hei 05-68577) and because the concentration of substrate is also as low as 0.1 to 0.5%. As the method in which high optical purities can be obtained by asymmetric reduction, the method using carbonyl reductase produced by Candida magnoliae (JP-A 2000-175693) was reported to synthesize (R)-propoxybenzene derivatives whose optical purities are 99% or more. However, this carbonyl reductase uses NADPH as a coenzyme. Therefore, synthesizing (R)-propoxybenzene derivatives using this enzyme requires addition and regeneration of NADPH, which is expensive and chemically unstable, and is industrially disadvantageous.